In this proposal, we will undertake a comprehensive approach to study the genetic basis of Vesicoureteral reflux (VUR). VUR has a prevalence of 1-2% in the Caucasian population and can account for up to 25-30% of pediatric and 10% of adult end stage renal disease (ESRD). Except for a few rare cases however, the specific genetic defects responsible for VUR are not known. To date, only a limited number of approaches have been explored to solve the genetic basis of VUR. In recent years, we have successfully applied GWAS, CNV analysis and exome sequencing to identify novel genes and loci for diverse renal and urological traits. Here, we will apply these approaches to resolve the genetic architecture of VUR. We hypothesize that familial VUR is genetically heterogeneous and caused by rare variants with large effect, which will be identifiable by linkage analysis combined with exome sequencing. Furthermore, we hypothesize that sporadic forms of VUR are produced by the combined effects of rare and common variants that will be detectable by GWAS methodology, CNV analysis and targeted resequencing of genes discovered in familial VUR. The study benefits from our own unique cohorts of patients with familial and sporadic VUR, multiple genotyped VUR cohorts contributed by collaborating institutions, as well as a national cohort contributed by the RIVUR study. In aim 1, we will identify rare mutations contributing to familial VUR by linkage analysis combined with exome sequencing in 50 kindreds. In aim 2, we will genotype the RIVU cohort and combine with other genotyped cohorts to identify rare genomic imbalances and common SNP variants for sporadic VUR. In aim 3, we will perform genotype-phenotype correlations of common and rare variants contributing to VUR.